The Matrix Biochemistry Unit has been directed by Dr Larry W. Fisher directly working with Dr. Abdullah Karadag (Research Fellow, VP) and an IPA, Dr. Neal S. Fedarko (JHU). Dr. Kalu Ogbereke, an oral pathologist and recent awardee of a NIDCR Clinical Research Fellowship, joined the team in late August 2002. We have continued to focus on structure-function studies of the noncollagenous proteins of bones and teeth, with particular emphasis on matrix protein-protein and matrix protein-cell interactions. It is highly likely that both the assembly of the matrix and its subsequent mineralization is controlled by cells via the use of some of these noncollagenous proteins. Other noncollagenous proteins are likely used in cell-cell and cell-matrix signal transduction. This year we have reached at least intermediate goals in several areas discussed below. One of the most abundant proteins in the mineralized matrices of bones and dentin is a protein we discovered several years ago, bone sialoprotein (BSP). It is a member of a family of proteins that we recently named the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family. We have discovered that the genes are clustered within a 375,000 basepair region of human Chromosome 4 and likely represent a series of gene duplications. As the family name implies, BSP is a phosphorylated, sulfated glycoprotein that binds to integrins, particularly the vitronectin receptor, through its RGD tripeptide. Although BSP in adults is generally limited to the skeleton, work with our colleagues has shown that this molecule is likely a very good marker for the appearance of many osteotrophic cancers including breast, lung, prostate and thyroid. Normal cells in these tissues do not produce BSP but it is strongly up-regulated as the cells become cancerous, particularly those that become metastatic. This year we published a manuscript in Cancer Research that showed that serum levels of BSP and/or another member of the SIBLING family, osteopontin (OPN), are elevated in lung, breast, prostate and colon cancers. In this paper we showed that the complex between the SIBLING and a protein (complement Factor H) found in all sera must be disrupted in order to properly measure the levels of BSP and OPN in patient sera. The NIDCR has applied for an international patent for this assay. We have shown that a third member of the SIBLING family, dentin matrix protein 1 (DMP1), can also bind to complement Factor H and protect some tumor cells from being killed by the complement pathway of our immune system. (Previously we have shown that BSP and OPN have this ability.) Furthermore, we have now shown that the mechanism for the protective properties of these proteins involves the complement protein, Factor I. We have proposed that this may be one mechanism that allows trophoblasts of the developing placenta to evade the complement system of the maternal blood supply and may also be similarly used by tumor cells during metastasis. We have also begun to study another member of the SIBLING family, dentin sialophosphoprotein (DSPP). Using our new antisera against this protein, our colleagues in the Skeletal Biology Section have been able to show that DSPP is expressed in their dental pulp stem cells upon transplantation in nude mice. This is strong evidence that the matrix made by these cells is authentic dentin perhaps opening the door to future use of pulp cells in repair of dental lesions. The Matrix Biochemistry Unit freely gives probes (antisera, cDNA, proteins etc.) to any laboratory in the world that makes a reasonable request. In FY02 we sent ~325 probes to 132 laboratories (~10% were in the dental field) around the world. Others in the Branch have sent these same probes during this time as well